Adverse drug reactions focus on clinical studies to connect possible side effects and the studied compound. Skin lesions often herald these reactions because this body organ can be quickly evaluated and confirmed to be immunologically active. These aspects make it particularly relevant in this and other clinical contexts. However, the skin condition itself can be highly non-specific, and it is always necessary to rule out other possible clinical causes, especially viral infections and drug vehicle allergies.

These skin reactions can be considered pharmacologically mediated (type A) or allergic or non-allergic hypersensitivity reactions (type B) (Böhm et al., 2018). Type A reactions, as they are generally dose dependent, can be resolved with changes in therapy and allow for the maintenance of treatment. On the other hand, Type B reactions constitute the minority, although they are more unpredictable than type A. Moreover, these responses can lead to severe conditions, such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS). In these cases, re-exposure to the potentially causative drug is strictly not recommended.

The most common form of drug rash is morbilliform or maculopapular (Hoetzenecker et al., 2016). Nonetheless, the same drug can cause different patterns of dermatological manifestation since the pathogenesis of pharmacodermia is multifactorial and may involve genetic factors, lymphocyte activation, metabolic enzyme defects, eosinophilia, herpes virus activation, among others. Regarding DRESS cases, it is believed that an allergic immune response to a particular drug can stimulate T cells and induce viral reactivation (Husain et al., 2013). In one of the present study cases, even though it was a mild skin reaction, positive IgM and IgG for Epstein–Barr may suggest a relationship between pharmacodermia and reactivation of herpes virus 7 (HHV-7).

We report four women, three patients without comorbidities, and one with diabetes using daily medications, who presented with skin rashes between 6 h and 9 days after starting CBD use. The experimental CBD studied was pharmaceutical grade with no other compound than the MCT oil vehicle. In total, 100 participants (79 women and 21 men) received CBD oil, with four skin reactions related to the medication use (4% of volunteers). Three main patterns were observed: exanthematous, monomorphic erythematous papular lesions, and urticarial pattern, on the trunk and abdomen, with centrifugal progression to the limbs, sparing the face and palmoplantar regions, which were pruritic or sensitive to touch. There was an association with headache and myalgia in one case and abdominal symptoms in two other cases. The suspension of CBD resulted in the involution of the lesions between 5 and 11 days, without any topical or systemic therapy for three of the patients and prednisone 0.5 mg/kg for 5 days for one of the patients. Subsequent re-exposure to CBD vehicle (MCT) for 5 days in two of the patients did not induce a recurrence of the rash.

A broad investigation of viral infections and serology for syphilis and hepatitis was carried out, which were negative, except for one of the patients who had positive serology for the Epstein–Barr virus. The relevance of research on arboviruses is worth noting since they are prevalent in the study region and on SARS-CoV-2, given the context of the COVID-19 pandemic. In addition, lesions were biopsied from three patients (cases 1, 3, and 4). The histopathological pattern showed skin with mild hyperkeratosis, dermal edema, focal vacuolar degeneration of the basal layer, and lymphohistiocytic infiltrate with sparse eosinophils predominantly in the perivascular and periadnexal locations (Figure 3). Given such clinical, laboratory, and anatomopathological findings, the four cases can be diagnosed as skin rashes induced by CBD use. To the best of our knowledge, these are the first case reports with multiple individuals not using other medications, with an extensive investigation to exclude other clinical causes and half of the patients being exposed only to the MCT vehicle afterward (Pettit et al., 2018; Singh and Antimisiaris, 2020).

An individual analysis of CBD plasma levels was only possible in two of the subjects since the other two withdrew from the trial before measurement. These two subjects showed levels that reached the upper 95% percentile of the whole study (levels of 98 and 179 ng/ml, respectively). This finding suggests that the reported pharmacodermia could be associated with high plasma levels of CBD. However, this possibility should be seen with caution, considering the low number of subjects. Also, the cutaneous rash did not occur in five other subjects that also reached similar high CBD plasma levels. CBD is extensively metabolized by CYP450 isoenzymes. The extent to which genetic polymorphisms in these isoenzymes would affect CBD plasma levels and their side effects remains poorly explored and should be a focus of future research.

Cannabis products are widely employed worldwide, and their use has been illegalized in several countries (Bonomo et al., 2018). After legalizing medicinal and recreational cannabis in some countries, its use highly increased (Wen et al., 2015; Martins et al., 2016; Hasin et al., 2017). In the United Kingdom, for instance, it is estimated that over a million people are using non-legally sourced cannabis for self-medication of diagnosed conditions (Schlag et al., 2021). CBD has gained special attention for its therapeutic potency for several neuropsychiatric and general medical conditions, including a trend as a new ingredient for skincare products. However, apart from epilepsy, much of the available data are from preclinical studies and lack the support of robust human, randomized, placebo-controlled, double-blind studies (Jhawar et al., 2019; Baswan et al., 2020).

While there is a growing demand in many countries for legal CBD use to treat various mental and physical health problems, determining the best regulatory response to these demands is a significant challenge. It occurs because most CBD products come in multiple formulations and routes of administration, and the great majority is prepared in an artisanal manner, without the necessary manufacturing, quality control, labeling, and pharmaceutical-grade production. In addition, there is a paucity of data to support the therapeutic use of many of the indications consumed by this tremendous global demand. The clinical use of CBD needs to be aligned with many other pharmaceutical products to ensure efficacy and safety for patients, given its interactions with other drugs and its potential side effect profile. Therefore, through evidence-based medicine, an exhaustive framework to guarantee the quality and safety of the CBD product is urgently needed to protect the consumers and minimize possible harm.